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Vioxx in Colorectal Cancer Therapy: Definition of Optimal Regimen - VICTOR
Description:
The goal of the analysis was to evaluate the frequency of cardiovascular thrombotic events with the cyclooxygenase-2 (COX-2) inhibitor rofecoxib compared with placebo among patients with colorectal cancer. The trial was designed to evaluate the effect of rofecoxib on reduction in tumor recurrence.
Study Design
Study Design:
Patients Enrolled: 2,434
Mean Follow Up: Median, 33 months
Mean Patient Age: Median, 65 years
Female: 36
Patient Populations:
Histologically proven colorectal carcinoma of stage III (any tumor stage, N1 or 2, and M0) or stage II (T3 or 4, N0, and M0) in patients who had undergone complete resection of the primary tumor without gross or microscopical evidence of residual disease; World Health Organization performance status 0 or 1; hematologic and biochemical function within the normal range; and completion of potentially curative therapy (surgery alone or surgery plus radiotherapy, chemotherapy, or both) within the prior 12 weeks
Exclusions:
Active peptic ulceration or gastrointestinal bleeding in the past year, a history of adverse reactions to nonsteroidal anti-inflammatory drugs (NSAIDs), known sensitivity to rofecoxib, use of long-term NSAID therapy (except for low-dose aspirin), age <18 years, history of cancer (other than adequately treated in situ carcinoma of the cervix or basal or squamous-cell carcinoma), inflammatory bowel disease, or severe congestive heart failure
Primary Endpoints:
Primary CV event endpoint: CV thrombotic events that were reported during treatment or within 14 days after the treatment period
Drug/Procedures Used:
Patients were randomized in a double-blind manner to rofecoxib (25 mg daily; n = 1,167) or placebo (n = 1,160). The trial was to enroll 7,000 patients, with half receiving study drug for 2 years and half for 5 years. However, the trial was discontinued early after the results of the APPROVe trial showed an increase in cardiovascular (CV) events associated with rofecoxib, and the drug was withdrawn from the market.
Principal Findings:
At the time of discontinuation of the trial, the median duration of treatment was 7.4 months in the rofecoxib group and 8.2 months in the placebo group; patients were followed for a median of 33 months total. The cancer was stage III in 52% of patients and stage II in 48%. Adjuvant chemotherapy was used in 65% of patients. History of diabetes was more common in the rofecoxib group than the placebo group (8.7% vs. 5.6%, p = 0.003).
Occurrence of CV thrombotic events reported during treatment or within 14 days after the treatment period were significantly higher in the rofecoxib group than the placebo group (n = 16 in 15 patients vs. n = 7 in 6 patients, hazard ratio [HR] 2.66, 95% confidence interval [CI] 1.03-6.86; p = 0.04). When evaluating all CV thrombotic events through the 2 years after trial closure, the excess risk with rofecoxib was not significant (HR 1.50, 95% CI 0.76-2.94; p = 0.24).
For the Antiplatelet Trialists’ Collaboration endpoint (the composite of death from CV, hemorrhagic, and unknown causes; nonfatal myocardial infarction [MI]; or nonfatal ischemic and hemorrhagic stroke) reported during treatment or within 14 days after the treatment period, the relative risk for rofecoxib was 1.60 (95% CI 0.57-4.51; p = 0.37); by trial end, the relative risk was 1.29 (95% CI 0.57-2.95; p = 0.54).
Interpretation:
Among patients with colorectal cancer, treatment with the COX-2 inhibitor rofecoxib was associated with an increased risk of CV thrombotic events through 14 days after study drug discontinuation compared with placebo.
While the overall number of events was small (23 events in 21 patients), the findings are consistent with other studies of rofecoxib such as APPROVe, which showed an increase in CV events with rofecoxib. Additionally, a meta-analysis of 121 trials demonstrated an approximate twofold increase in the risk of MI with use of selective COX-2 inhibitors compared with placebo. In the present study, the risk of an increase in CV events emerged despite a relatively short treatment period, with rofecoxib used for a median of 7.4 months. Only 33% of patients received the study drug for 12 months or longer in the trial.
References:
Kerr DJ, Dunn JA, Langman MJ, et al. Rofecoxib and cardiovascular adverse events in adjuvant treatment of colorectal cancer. N Engl J Med 2007;357:360-9.
Keywords: Risk, Myocardial Infarction, Stroke, Cyclooxygenase 2 Inhibitors, Lactones, Reference Values, Chemotherapy, Adjuvant, Colorectal Neoplasms, Confidence Intervals, Neoplasm Recurrence, Local, Sulfones, Diabetes Mellitus
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